Pancreatic cancer (PC) is a highly aggressive cancer with a dismal 5-year survival rate of < 5%. Current systemic standard chemotherapies provide marginal benefits to the patient, only prolonging survival for few weeks. Hence, developing novel preventive strategies for PC assume increase importance, with the development of novel chemopreventive agents being the most critical component. We propose to study two novel agents [phospho-valproic acid (P-V) and phospho-aspirin (P-A)], as a new drug combination for PC prevention. Recently, we showed that P-V strongly inhibits PC growth in multiple preclinical models of PC (up to 97% reduction compared to controls. P-V is safe, as shown by genotoxicity and animal toxicity studies, and mitochondrial STAT3 is its key molecular target. On the other hand, P-A is a strong inhibitor of EGFR activation and reduces PC xenograft growth by 78% compared to control. Remarkably, when given in combination, P-A and P-V prevented the development of pancreatic carcinoma by 95% (p<0.01) in mice with activated Kras. Objective/Hypothesis: Our overall goal is to develop an effective drug combination for the chemoprevention of PC. Particular emphasis is placed on the involvement of mitochondrial STAT3 and EGFR signaling, which are essential for pancreatic carcinogenesis and are targeted by P-V and P-A. Our hypothesis is that the P- V/P-A combination is efficient in PC prevention, acting synergistically on the mitochondrial STAT3 and EGFR pathways. Specific Aims: We will pursue the following aims: Aim #1: To evaluate the safety, metabolism and pharmacokinetics of the P-V/P-A combination in preclinical models of PC; Aim #2: To determine the efficacy of the P-V/P-A combination in preclinical models of PC; Aim #3: To determine the mechanism of action of the P- V/P-A combination in vitro and in vivo. Study design: Our studies will involve the evaluation of the safety, metabolism, pharmacokinetics and efficacy of the novel drug combination in multiple distinct, yet complementary, preclinical models of PC and the assessment of the mechanism of action of this novel drug combination. Cancer relevance: At the completion of these studies, we expect to have determined key pharmacological parameters of a promising novel drug combination against PC. Given the lack of effective agents against PC, we believe that the proposed work holds the promise of a significant advance in this area.